Congenital kidney malformations are the major cause of chronic renal failure during early childhood and abnormal nephrogenesis is causally linked to the development of adult hypertension. Recent studies have demonstrated that inactivation of the genes encoding components of the renin-angiotensin system (RAS) in mice causes a range of congenital anomalies of the kidney and urinary tract including papillary hypoplasia, hydronephrosis and urinary concentrating defect. This suggests that an intact RAS is required for distal nephron/ureteric bud morphogenesis and function. Accordingly, the primary objective of this proposal is to elucidate the role of the RAS in the ontogeny of the distal nephron. Preliminary results included in this proposal indicate that angiotensinogen, angiotensin II type 1 and type 2 receptors and angiotens in converting enzyme are all expressed in embryonic mouse ureteric bud (UB) cells. This may explain why RAS inactivation leads to abnormal development of the renal medulla. We hypothesize that the developing distal nephron expresses a functional RAS that regulates branching morphogenesis and/or tubulogenesis. This hypothesis will be tested in 3 specific aims. Specific Aim 1 is to demonstrate that the developing distal nephron expresses all the components of the RAS. Specific Aim 2 is to characterize the effects of angiotensin II on ureteric bud branching and tubulogenesis in vitro. Specific Aim 3 is to determine the intracellular signaling pathways and secreted molecules that mediate angiotensin II-induced tubulogenesis. The proposed studies will open new avenues in RAS research as related to kidney development and the results may lead to potentially new intervention strategies for the prevention and treatment of congenital renal disease.